CN116115554A

CN116115554A - Method and system for forming dosage forms in packages

Info

Publication number: CN116115554A
Application number: CN202310287787.3A
Authority: CN
Inventors: L·E·比奇-赫雷拉; M·F·博尔特; T·J·布拉德伯里; H·卡布拉尔; K·E·卡普托; W·R·格罗斯; M·李; M·R·帕特尔; A·M·菲利普斯; T·S·特雷西; T·G·韦斯特; J·于
Original assignee: Aprecia Pharmaceuticals Co
Current assignee: Aprecia Pharmaceuticals Co
Priority date: 2018-10-15
Filing date: 2019-10-15
Publication date: 2023-05-16
Also published as: MX2021004318A; CA3115574A1; US20210393533A1; JP2022508714A; KR20210075163A; CN112867482A; US20220183986A1; EP4140477A1; EP3866757A1; WO2020081561A1; CN112867482B; AU2019359810A1; BR112021006668A2; SG11202103708RA; US11278501B2; EP3866757B1; ES2930199T3

Abstract

A method and system for forming a pharmaceutical dosage form within a portion of a blister package. The method comprises the step of providing a blister package for a dosage form having a recess. A predetermined amount of a drug-containing powder material comprising drug-containing particles is deposited as a substantially uniform powder layer within the recess. A binding liquid is then deposited in a pattern on the powder layer within the recess to bind the particles of the powder layer and form an incrementally wetted layer. Excess solvent in the bonding material may be removed to form an incremental bonding layer. These steps are repeated sequentially at least one or more times to form a pharmaceutical dosage form within the blister package.

Description

Method and system for forming dosage forms in packages

The present application is a divisional application of the invention patent application filed on 10/15 2019 with application number "201980068020.3" entitled "method and System for Forming dosage forms in a Package".

Technical Field

The present invention relates to the field of manufacturing dosage forms or tablet forms of pharmaceuticals or other active ingredients.

Background

In recent years, pharmaceutical manufacturers have used blister packages for the formation and dispensing of pharmaceutical tablets. These blister packages are typically composed of a blister sheet or blister film and a lidding sheet. The blister sheet contains spatial depressions for holding individual doses, including tablets, capsules, pills, and the like.

In a standard method for manufacturing lyophilized tablets, a single dose in liquid form is introduced into each recess of a blister sheet. The blister sheet is then placed with the liquid formulation in a refrigerated environment where the formulation is subjected to low temperatures to freeze it. The blister sheet is then transferred to a freeze dryer where the ice is removed by sublimation. After freeze drying is completed, the flakes are removed from the drying chamber and covered with an adhesive cover sheet that encloses the solid agent in respective individual recesses. International publication WO/1994/012742 is incorporated herein by reference as a teaching, in particular as a known method for manufacturing freeze-dried tablets in blister packs.

Nevertheless, freeze-drying or lyophilization processes can have significant negative impact on product activity, shelf stability, and batch consistency and reproducibility. This process is inherently expensive in terms of energy and human resources, and quality control and regulatory requirements present additional challenges. In some cases, the lyophilization or freeze-drying process is not at all suitable for a particular drug or drug product.

Rapid prototypes describe various techniques for manufacturing three-dimensional prototypes of an object from a computer model of the object. One technique is three-dimensional printing, in which a printer is used to fabricate 3-D prototypes from multiple two-dimensional layers. In particular, a digital representation of the 3-D object is stored in a computer memory. Computer software divides the representation of the object into a plurality of different 2-D layers. Alternatively, the instruction stream (sequential sequence) for each delta layer, such as a sequence of images, may be directly input. The 3-D printer then makes a thin layer of adhesive material for each 2-D image layer of the software division. These layers are printed together layer by layer and adhered to each other to form the desired prototype.

Powder-liquid three-dimensional printing techniques have been used to prepare articles such as pharmaceutical dosage forms, mechanical prototypes and conceptual models, molds for casting mechanical parts, bone growth promoting implants, electronic circuit boards, scaffolds for tissue engineering, responsive biomedical composites, tissue growth promoting implants, dental restorations, jewelry, liquid filters and other such articles.

Three-dimensional printing may include solid freeform fabrication/rapid prototyping techniques in which a thin layer of powder is spread onto a surface and selected areas of powder are bonded together by controlled deposition ("printing") of a liquid. This basic operation is repeated layer by layer, with each new layer being formed over and adhered to the previously printed layer to finally make a three-dimensional object (object) in the unbound powder bed. When the printed objects have sufficient cohesion, they can separate from the unbound powder.

Systems and apparatus assemblies for three-dimensional printing of articles are commercially available and may also be used by others, for example: three-Dimensional Printing Laboratory (Cambridge, mass.) from the university of Massachusetts, 3DP and HD3DP from Z Corporation (now part of 3D Systems) ^TM Systems (burlington, ma), the Ex One Company, l.l.c. (euler, pa), soligen (northly, ca), specific Surface Corporation (franklin, ma), TDK Corporation (qian-leaf county, japan), therics l.l.c. (akren, ohio, now part of Integra Lifesciences), phoenix Analysis&Design Technologie (Tanpei, arizuna), dimension of Stratasys, inc ^TM System (Eden Prairie, minnesota), object geometry (Billerica, massachusetts or Israel Huo Wote)), xpress 3D (Minnesota Abolis, minnesota) and Invision of 3D Systems ^TM System (banrensia, california).

Three-dimensional printing systems employing powders and a binding liquid typically form an article by depositing the binding liquid onto each of the sequentially applied powder layers. A bonding liquid is applied in a pattern to predetermined areas of the powder in each powder layer such that unbound powder material remains on the outer periphery of the pattern. Unbound powder typically surrounds the printed article being formed. The printed article containing the cohesive powder is then separated from the bulk of the unbound powder. Such a process undesirably wastes or recycles unbound powder. It would be a great improvement in the art to provide apparatus assemblies, systems, and methods that substantially reduce or eliminate the need to waste or recycle unbound powder.

U.S. patent publication 2018/0141275 (the disclosure of which is incorporated herein by reference) describes a manufacturing system, an apparatus assembly, and its use in preparing an article by cavity three-dimensional printing. The cavity may be part of a build module on the machine within which items are formed that approximate the circumference of the cavity (periherey). The article is formed by a continuous plurality of incremental layers formed within the cavity. After completion, the 3DP article was ejected from the chamber. The 3DP article is optionally dried, optionally dedusted, and/or optionally packaged.

Thus, there remains a need for improved and more convenient pharmaceutical dosage forms and methods of preparing the same.

Disclosure of Invention

The present invention provides a method and system for forming a cohesive powder or cohesive particulate article in a volume of a recess of a packaging material, and a method and system for manufacturing an article formed in situ in a recess of its packaging. In some embodiments, the article is a dosage form, which may be a medicament, drug, or tablet or pill, including solid oral prescription drugs. The method described herein is also referred to as intaglio three-dimensional printing or intaglio 3DP. The package may include one or more recesses, and in some embodiments a plurality of recesses arranged in a pattern. The method and system can be used for high-yield continuous, semi-continuous or batch production, and has the advantages of minimum product loss, high efficiency and high product repeatability.

The embodiments and features described herein provide a method of forming pharmaceutical and drug-containing tablets directly within a package, such as a blister package, and in particular embodiments, a method of preparing rapidly disintegrating tablets in a disposable single dose blister package.

Embodiments described herein may provide for significant reduction or elimination of waste or recyclable unbound powder as compared to other three-dimensional printing (3 DP) processes. The recess 3DP comprises most, substantially all or all of the particulate material entering the recess in a corresponding single 3-D printing dosage form.

Embodiments described herein provide a method of forming a dosage form within a portion of a package for the dosage form. The method comprises the following steps: 1) Providing a portion of a package for a dosage form, the portion of the package comprising at least one recess; 2) Depositing a predetermined amount of powder material comprising particles into a powder layer within the at least one recess; 3) Depositing a bonding liquid in a pattern on the powder layer within the at least one recess to bond at least a portion of the particles of the powder layer to form an incremental bonding layer; 4) Sequentially repeating steps 2) and 3) at least one or more times to form a dosage form within the portion of the package for dosage forms.

Embodiments described herein also provide a method of forming a dosage form within a portion of a package for a dosage form, comprising the steps of: 1) Providing a portion of a package for the dosage form comprising at least one spatial recess; 2) Depositing a predetermined amount of powder material comprising particles into a powder layer within the at least one recess; 3) Depositing a bonding liquid in a pattern on the powder layer within the at least one recess to bond at least a portion of the particles of the powder layer to form an incremental wetting layer; 4) Sequentially repeating steps 2) and 3) at least one or more times to form a dosage form within the portion of the package for dosage forms.

In some embodiments, the deposited powder layer is a substantially uniform powder layer.

In one or both of the above methods, the powder material may be deposited into at least one recess in a powder deposition area (or system) of the device or system component, and the powder material may be layered, or form incremental layers of powder material, in a powder deposition area (or system) of the device or system component, or in a dedicated powder leveling area (or system). The binding liquid may be applied to the incremental powder layers while the container is in the binding liquid application zone (or system) of the device or system assembly. The shaping or tamping of the layer of powder material or wetting material may be done in a powder deposition area (or system) or a powder leveling area (or system) of the device or system component, or in a dedicated shaping area (or system) of the device or system component.

The dosage form packages containing one or more recesses may be moved between any two or more of the above-described regions (or systems) in any order. In some non-limiting embodiments, the receiver moves: a) Repeatedly moving from the powder deposition zone to the bonding liquid application zone and then optionally to the forming zone; b) Moving from the powder layering zone to the forming zone and then to the bonding liquid application zone; c) Moving from the powder layering zone to the bonding liquid application zone, then back to the powder layering zone, and then back to the forming zone; or d) from the powder layering zone to the leveling zone to the bonding liquid application zone to the drying zone. The discharge zone may be located after the powder stratification zone, bonding liquid application zone, forming zone and/or drying zone.

The package of the article of manufacture may include a film material having one or more recesses therein containing a shaped adhesive powder formulation formed within the one or more recesses, and a peelable or removable cover sheet adhered to the film material to encapsulate the formulation within the one or more recesses.

In one embodiment, the dosage form is a coherent powder matrix formed within the one or more recesses by binding powder deposited within the one or more recesses with a binding liquid.

In one embodiment, a portion of the shaped cohesive powder matrix conforms to the inner surface of the one or more recesses.

Embodiments may also provide a package comprising a film material having one or more recesses therein, the one or more recesses containing a shaped cohesive powder matrix formed within the one or more recesses, and a peelable or removable cover sheet adhered to the film material to encapsulate the cohesive powder matrix within the one or more recesses.

In an embodiment, the bonded powder matrix is formed within the one or more recesses by bonding powder deposited within the one or more recesses with a bonding liquid. A portion of the shaped, bonded powder matrix may conform to an inner surface of the one or more recesses. The peripheral portion of the bonding powder matrix facing the inner surface of the one or more recesses may contain an additional amount of bonding liquid.

In an embodiment, the bonding powder matrix comprises a 3D printed rapidly disintegrating dose and may be formed within the one or more recesses by bonding powder deposited within the one or more recesses with a bonding liquid.

In one embodiment, the cohesive powder matrix comprises an active pharmaceutical ingredient (APT).

In another embodiment, a peripheral portion of the inner surface of the bonding powder matrix facing the one or more recesses comprises an additional amount of bonding liquid.

In an embodiment, the at least one recess has a fixed shape and volume that does not change or change under normal use and handling of the package.

In one embodiment, the package includes one or more blisters, cups, pods, or other containers.

In one embodiment, the package is preformed and/or precut prior to the dosage form forming process.

In an embodiment, the package comprises a sheet comprising a plurality of recesses formed in the sheet, and wherein the recesses comprise side walls extending from the sheet to the closed end.

In an embodiment, step 4) is repeated at least three times.

In an embodiment, a portion of the powder material comprises particles of a binder material, and the binding liquid binds the particles of the binder material.

In an embodiment, the method may comprise the step of depositing a bonding liquid at least on the closed end of the recess prior to step 2).

In one embodiment, the at least one recess includes an inner surface that includes a release agent.

In an embodiment, the bonding liquid comprises a volatile solvent, and the method may include the step of evaporatively removing a portion of the volatile solvent from the incremental bonding layer.

In an embodiment, the sidewall has a recess depth, and the thickness of each powder layer is at least 5% and up to about 100% and in some embodiments, up to about 50% of the recess depth.

In some embodiments, the number of powder layers deposited into the recess and formed as incrementally bonded powder layers may be one or more layers, including two or more layers, three or more layers, four or more layers, five or more layers, six or more layers, seven or more layers, or eight or more layers, and up to fifty or less layers, forty or less layers, thirty or less layers, twenty or less layers, eighteen or less layers, sixteen or less layers, fourteen or less layers, twelve or less layers, ten or less layers, eight or less layers, six or less layers, or four or less layers, in any combination.

The incremental powder layers may have a target or weight average thickness (weight average thickness) of a predetermined thickness (vertical height). In some embodiments, the predetermined thickness may vary from 0.005 to 0.015 inches, from 0.008 to 0.012 inches, from 0.009 to 0.011 inches, about 0.01 inches, 100-300 μm,100-500 μm, about 200 μm, or about 250 μm. In some embodiments, the thickness of the incremental powder layers is in the range of 100-400 microns, 150-300 microns, or 200-250 microns. In one embodiment, the powder layer has a thickness of 200 microns. In another embodiment, the powder layer has a thickness of 250 microns.

In some embodiments, the predetermined thickness is at least 0.05 inch, at least 0.008 inch, at least 0.010 inch, at least 0.012 inch, at least 0.014 inch, or at least 0.016 inch, and up to 0.020 inch, up to 0.018 inch, up to 0.016 inch, up to 0.014 inch, up to 0.012 inch, or up to 0.010 inch. As thicker incremental layers are used, more and more printing fluid is deposited on the layer to ensure adequate adhesion both in the plane of the layer and from layer to layer. Conversely, for thinner incremental layers, a smaller amount of printing liquid will be deposited to achieve the same degree of adhesion. The use of a larger layer thickness for a given amount of printing liquid deposited per layer will reduce (deteriorate) the operability of the dosage form and shorten (improve) the dispersion time. If too thick a layer is used for a given amount of fluid, lamellar defects may form, resulting in the dosage form being prone to fracture (delamination) along the plane of the layer, or the dosage form itself may not have sufficient strength to handle at all.

The diameter (equivalent diameter of the non-circular region) of the dosage form produced by the 3DP process described herein may range from about 13-14mm to about 20-25mm, and the height (total thickness) may range from about 5-6mm to about 8-10 millimeters.

In an embodiment, the pattern of bonding liquid deposited on the powder layer has a periphery arranged against or in contact with the side wall of the package.

In an embodiment, the pattern of binding liquid deposited on the powder layer has a shape selected from the group consisting of an annular ring and a circle.

In one embodiment, the method may include the steps of: a capping layer is applied over the dosage form and the at least one recess to form a sealed package for the dosage form.

In one embodiment, the bonding liquid is deposited by ink jet printing to form a wetted or bonded powder layer.

In an embodiment, the step 2) of depositing a predetermined amount of powder material comprising particles into a substantially uniform powder layer within the at least one recess comprises: 1) Depositing a predetermined amount of powder material comprising particles into the at least one recess, and 2) forming the deposited predetermined amount of powder material into a substantially uniform powder layer within the at least one recess.

In an embodiment, the forming step includes shaping and/or ramming a deposited predetermined amount of powder material into a formed powder layer having an upper surface. In another embodiment, the forming step includes tamping the last deposited predetermined amount of powder material into a newly formed powder layer having an upper surface.

In one embodiment, the method includes, after the step of depositing the bonding liquid in a pattern on the powder layer within the at least one recess: and (d) shaping and/or tamping the incremental wetting layer into a shaped or compacted wetting layer. The wetting layer is formed to have an upper surface that is planar or planar in one embodiment and convex or concave in another embodiment.

In an embodiment, the method comprises the following steps after forming the plurality of incremental wetting layers into a wetting structure comprising the plurality of wetting layers: shaping and/or tamping the plurality of wetting layers into a shaped or compacted wetting structure.

In one embodiment, the forming and/or tamping steps employ a tamper or tamper. In some embodiments, the tamper has a concave surface.

In one embodiment, the powder material may comprise one or more types of drug-containing particles.

The present invention may also provide a 3DP device system and assembly for providing and positioning recesses or recesses arranged in a pattern, for example in connection with dosage form packaging, and for forming a 3DP dosage form within the recesses. The device system and components may include, but are not limited to: a powder deposition system disposed in the powder deposition zone, a powder leveling system disposed in the powder leveling zone, a bonding liquid application system disposed in the bonding liquid application zone, a forming system disposed in the forming zone, and a drying system disposed in the forming zone.

In some embodiments, the 3DP device assembly may include a control system including one or more computerized controllers, one or more computers, and one or more user interfaces for the one or more computers. In some embodiments, one or more components of the device assembly are computer controlled. In some embodiments, one or more components of the 3DP build system are computer controlled. In some embodiments, the powder deposition system, the powder leveling system, the bonding liquid application system, the forming system disposed in the forming zone, and the drying system are computer controlled.

In some embodiments, the 3DP device assembly may further include one or more harvesting systems, one or more liquid removal systems, one or more powder recovery systems, one or more article transfer systems, and one or more inspection systems. The 3DP device assembly, apparatus or system may include some or all of the above systems. For example, in certain embodiments of the lumen 3DP device assembly, device or system, it is not necessary to have a collection system because substantially all of the powder material entering the recess is contained in the corresponding dosage form formed within the recess with little or no excess powder to be separated.

Drawings

Fig. 1 shows a blister package with a portion of the lidding sheet peeled away, showing the dosage form located within the recess.

Fig. 2 shows a cross-sectional view of a dosage form within a recess covered with a cover sheet.

Fig. 3 shows a cross-sectional view of the dosage form within the recess, with the lidding sheet removed.

Fig. 4 shows a cross-sectional view of the recess from which the dosage form has been removed.

Fig. 5 shows that the bonding liquid is deposited on the closed end of the recess.

Fig. 6 shows the deposition of a stack of powder material from a powder source into a recess.

Fig. 7 shows an example of a dosing device that may deliver a predetermined amount of powder material within a recess of a blister pack, including, but not limited to, by a predetermined mass weight and by a predetermined volume.

Fig. 8 shows a cross-sectional view of the dosing device of fig. 7 positioned to deposit a predetermined amount of powder material onto the cohesive powder layer in the recess of the blister pack.

Fig. 9 shows the dosing device of fig. 7, wherein the filling chamber containing a predetermined amount of powder material is isolated from the powder supply.

Fig. 10 shows the dosing device of fig. 7, wherein a predetermined amount of powder material is being deposited into the recess.

Fig. 11 shows a rotational dosing device for dispensing powder material into recesses in a blister sheet 2.

Fig. 12A shows a front cross-sectional view through the rotational dosing device and blister sheet of fig. 11.

Fig. 12B shows a front cross-sectional view through another embodiment of the rotational dosing device and blister sheet.

Fig. 13 shows a- > kinetic metering device for filling a plurality of recesses in a metered dose package, including a volume dispensing recess.

Fig. 14 shows a front cross-sectional view through the automatic dosing device and the volume dispensing recess of fig. 13.

Fig. 15 shows a front cross-sectional view through the automatic dosing device and the volume dispensing recess of fig. 14, wherein the powder tank and the filling recess are filled with powder material.

Fig. 16 shows the automatic dosing device of fig. 15, wherein the filled recess is moved from the filling position towards the dispensing position and the filled recess partially overlaps the dispensing opening.

Fig. 17 shows the automatic dosing device of fig. 16, wherein powder material is discharged from the filling recess and dispensed into the aligned recesses.

Fig. 18 shows the automatic dosing device of fig. 17, wherein the empty recess of the blister sheet is moved to a position aligned with the dispensing opening.

FIG. 19 illustrates another embodiment of an automatic dosing device for filling multiple recesses in a dosing package, including a volume dispensing recess and a tamper.

Fig. 20 shows a front cross-sectional view through the automatic dosing device and the volume dispensing recess of fig. 19.

Fig. 21 shows a front cross-sectional view through the automatic dosing device and the volume dispensing recess of fig. 20, wherein the powder tank and the filling recess are filled with powder material.

Fig. 22 shows the automatic dosing device of fig. 21, wherein the powder material is substantially emptied from the filling recess and dispensed into the aligned recess.

FIG. 23 shows the automatic dosing device of FIG. 22 with the tamper extending through the fill cavity and the dispensing opening.

Figure 24 shows the automatic dosing device of figure 23 with the tamper retracted and the empty recess of the blister sheet moved into alignment with the dispensing opening.

Fig. 25 illustrates various means for dispersing a stack of powder material into a substantially uniform layer by shaking and/or oscillating the recess.

Figure 26 shows a support plate having openings aligned with the recess pattern of the blister package.

Figure 27 shows a support plate having openings aligned with the pattern of recesses of the blister package, and a vacuum means for securing the blister sheet to the support plate.

Fig. 28 shows a vibrating device oscillating sideways to flatten the powder material in the recess of the blister sheet.

Fig. 29 shows a brush assembly for flattening the powder pile in the recess of fig. 28.

Fig. 30 shows the brush assembly of fig. 29 lowered into a powder pile.

Fig. 31 shows the brush assembly of fig. 29 throwing particles of powder radially outward toward the wall of the recess.

Fig. 32 shows the brush assembly being removed from within the recess after the powder pile has been formed into a substantially uniform powder layer.

Fig. 33 shows a layer deposition apparatus positioned to collect a quantity of powder material from a powder hopper.

Fig. 34 shows a vacuum being applied to the layer deposition apparatus of fig. 33 to fill the inlet end with a volume of powder from the powder hopper.

Fig. 35 shows that the applied vacuum maintains the volume of powder within the inlet of the layer deposition device after lifting the layer deposition device from the powder hopper.

Fig. 36 shows a layer deposition device holding the volume of powder when positioned over the recess.

Fig. 37 shows a volume of powder held in the inlet with the layer deposition device positioned within the recess.

Fig. 38 shows that the volume of powder is deposited in the recess as a uniform powder layer after the vacuum is removed and the layer deposition device is lifted from the recess.

Fig. 39 shows an alternative embodiment of a layer deposition device that provides an additional powder volume at the periphery of the powder absorption volume space.

Fig. 40 shows the layer deposition apparatus of fig. 39 positioned within a recess.

Fig. 41 shows that the volume of powder and the additional peripheral volume of powder are deposited in the recess as a uniform powder layer after the vacuum is removed and the layer deposition device is lifted out of the recess.

Fig. 42 shows the application of a binding liquid to a uniform powder layer to form a wetted powder layer.

Fig. 43 illustrates several means for applying heat to a wetted powder layer to remove excess solvent liquid, drying the wetted powder layer and forming a cohesive powder layer.

Fig. 44 shows a hot air dryer for evaporating moisture and solvent from a wetted powder layer.

Fig. 45 illustrates depositing a powder material into the recess to form a second substantially uniform powder layer on the first bonded powder layer.

Fig. 46 shows the application of a bonding liquid to a second substantially uniform powder layer to form a second wetted powder layer.

Fig. 47 shows a substantially uniform powder layer forming the uppermost layer on a previously deposited, wet and dry incremental bond powder layer.

Fig. 48 shows the application of a bonding liquid to the uppermost substantially uniform powder layer to form the uppermost wetted powder layer.

Fig. 49 shows that the uppermost wetting powder layer has been dried to the uppermost adhesive layer and the lidding sheet has been applied and sealed over the completed dosage form within the recess.

Fig. 50 shows an alternative embodiment in which the bonding liquid is applied only at peripheral portions of the second substantially uniform powder layer, leaving a central portion of the non-wetted/non-bonded powder.

Fig. 51 shows the application of a third substantially uniform powder layer over the second layer shown in fig. 50 having an unwetted and unbonded powder center portion.

Fig. 52 shows the application of a bonding liquid on a third substantially uniform powder layer to form a third wetted powder layer on a second layer having a central portion of non-wetted and non-bonded powder.

Fig. 53 shows that the third uppermost wetting powder layer has been dried to a third binding layer.

Fig. 54 shows an alternative embodiment in which the bonding liquid is applied only at the peripheral portion of the first powder layer to form an outer coating at the peripheral or edge portion of the first powder layer.

Fig. 55 shows that a bonding liquid is applied onto a central portion of a first powder layer to form a first wetted powder portion surrounded by a coating at a peripheral or edge portion of the first powder layer.

Fig. 56 shows the application of a bonding liquid at a peripheral portion of the uppermost substantially uniform powder layer to form an outer coating at the peripheral or edge portion of the uppermost powder layer.

Fig. 57 shows the application of a bonding liquid on top of a substantially uniform powder layer of an uppermost layer to form an uppermost wetted powder layer with a peripheral outer coating.

Fig. 58 shows that the uppermost wetting powder layer has been dried to the uppermost bonding layer and a bonding liquid has been applied to the top portion of the uppermost powder layer to form the wetting coating.

Fig. 59 shows the final dosage form after drying or curing the wet coating on the top portion of the uppermost powder layer to form an outer coating surrounding the incrementally bonded powder layer.

FIG. 60 shows a tamper having a concave bottom surface positioned above a top layer of powder material in a recess.

Fig. 61 shows the tamper positioned in the recess and pressed down on the upper surface of the powder layer.

Fig. 62 shows a convex upper surface of the uppermost powder layer, which is shaped by a tamper.

Fig. 63 illustrates the deposition of a binding liquid onto a convex powder material to form a final, shaped wetting powder layer.

Fig. 64 shows the uppermost wetting powder layer to form the uppermost wetting powder layer.

Fig. 65 shows a tamper for shaping the uppermost wetted powder layer of fig. 64.

Fig. 66 shows a rotary tamping device with a tamper for tamping a powder layer in recesses of a blister sheet arranged in a pattern.

Fig. 67 shows a front cross-sectional view through the rotary tamping device and blister sheet of fig. 66.

Fig. 68 illustrates a linear 3DP device assembly including a powder tank and a rotary metering device, a powder leveling device, a printing device, and a drying device.

Fig. 69 shows a 3DP device assembly having two assemblies in series, each arranged as a continuous loop comprising a powder tank and a rotary dosing device, a powder leveling device, a printing device and a drying device.

Fig. 70 shows a 3DP device assembly with a continuous loop conveyor consisting of a powder tank and a rotary dosing device, a powder leveling device, a printing device and a drying device on different parts of the endless conveyor.

Fig. 71 shows a 3DP device assembly having first and second continuous loops with a common conveyor section comprising a powder tank and a rotary dosing device and a printing device. The powder leveling device and the drying device are positioned along the outer loops of the respective first and second continuous loops.

Fig. 72 shows a 3DP device assembly 50 having a first continuous loop sharing a common conveyor section. The first continuous loop includes a powder dispensing device and a leveling device along the outer portion, and the second continuous loop includes a printing device and a pair of drying devices.

Detailed Description

Definition:

as used herein, the term "recess" refers to a spatial cavity formed in a portion of a package for a dosage form. Non-limiting examples of recessed portions of the package include blisters, cups, pods, or other packaging containers capable of receiving and holding flowable materials (e.g., powders or liquids).

As used herein, "3DP" refers to three-dimensional printing, or the like.

As used herein, the term "tamping" refers to the act of reducing the porosity or pore volume within the volume of a mass of powder under a force that reduces the volume of the mass. Compaction may be achieved by a compactor system whereby the volume of the incrementally formed powder layer or layers formed within the recess is shaped and/or reduced.

As used herein, "shaping" refers to the act of changing the shape of one or more surfaces or the shape of one or more layers of an incremental layer of material. The change in shape may be a change in shape of the entire surface or only a portion of the surface, and is typically the upper surface in the forming step. The altered shape may be flat or planar, convex, concave or any other shape desired. The altered shape of the upper surface may be different from the shape of the lower surface.

The process of the present invention may include one or more tamping steps, one or more shaping steps, and/or one or more marking steps.

As used herein, a "three-dimensional print build system" or "3DP build system" generally includes a powder layering system (region) in which powder material is deposited and/or layered into incremental powder layers within recesses, and a printing system (region) in which a bonding liquid is applied to the incremental powder layers according to a predetermined pattern, thereby forming a partially or fully bonded powder layer (incremental print layer).

Fig. 1 shows a blister package 1 comprising a blister sheet 2 in which a desired number of recesses 4 are formed in a sheet 6 of a desired film or laminate by conventional cold forming. The lidding sheet 8 is shown not sealed to sheet 6, including at location 3 (also shown in the cross-sectional view of fig. 2) at the recess containing dosage form 10. The front portion of blister package 1 shows lidding sheet 8 folded back over sheet 6 to reveal dosage form 10 disposed within recess 4 (as shown in the cross-sectional view of fig. 3) or to remove dosage form 10 from recess 4 (as shown in the cross-sectional view of fig. 4). The size and shape of the recess 4 is optional and may be determined by the size and nature of the tablet to be formed and other factors known to those skilled in the art. The number and arrangement of recesses 4 in the blister sheet 2 is a matter of choice or choice, which may be based on the dosage and time of administration of the tablet, economy and type of API active in the case of a drug or tablet, among other considerations well known to those skilled in the art. The film or laminate 6 comprises a formable material in which the one or more recesses may be formed. In one embodiment, the film or laminate 6 may comprise a thermoformable plastic layer, for example, a polymer comprising polyamide, polyvinyl chloride, polypropylene, or other such substances. In another embodiment, the film or laminate 6 may comprise a cold formable metal foil, such as an aluminum film. The laminate may comprise two or more layers which may be made of the same or different materials and of the same or different thickness. The thickness of the film or laminate may be between 25 and 100 micrometers (μm).

Fig. 4 shows a single part of a blister pack for dosage forms, consisting of a recess 4 formed in a sheet 6, and having a closed end 7 and an outer wall 9 defining a space 5 within the recess 4. In the non-limiting embodiment, the recess 4 in the blister sheet 2 is shown to have a circular planar shape and an outer wall that tapers inwardly from the sheet towards the closed end 7. Some embodiments of the recess in the blister sheet package have an elongated shape or a complex shape. Some embodiments have an outer wall that is circular, arcuate, or perpendicular to the packaging sheet. Those of ordinary skill in the art will recognize and appreciate that any embodiment of a packaging material or any type, shape, or size of recess may be directly and specifically combined with any other embodiment associated with the invention described herein.

Fig. 5 shows an initial (but in some embodiments optional) step of depositing an initial layer 31 of binding liquid onto the bottom or closed end 7 of the recess 4 to provide a binding of the initial powder material 20 deposited into the recess 4. The initial layer 31 of bonding liquid may be deposited by, for example, ejecting droplets 30 of bonding liquid from the printing nozzles 32 of an inkjet printing nozzle assembly 33. An initial layer or film of binding liquid ensures that the bottom surface of dosage form 10 firmly binds the particles along bottom surface 12. In some embodiments, an excess of binding liquid is used, more than at least an amount sufficient to bind the particles of powder material together, to form a wet coating that, when dried or cured, forms a hard, resilient base coat. In some embodiments, the bonding liquid used to form the wet coating is a different liquid than the bonding liquid used to form the bonding powder layer.

Fig. 6-24 illustrate a method and apparatus for depositing powder material into one or more recesses of a blister pack.

Fig. 6 shows a step 40 of depositing a first predetermined amount of powder material 20 comprising particles within the recess 4 or within each of the plurality of recesses 4. Powder 20 is discharged from a feed container or hopper 22 by a powder metering device 24. The powder metering device 24 is designed and configured to dispense a predetermined volume of powder 40 from the feed container 22, which may include a predetermined volume of powder or a predetermined mass of powder. In the embodiment shown, a predetermined amount of powder 40 is deposited on the closed end 7 of the recess 4 in the form of a powder pile 40. The bottom of the first deposition stack 40 of powder 20 is wetted with an optional initial layer 31 of binding liquid as shown in fig. 5 to form a coating 50 on the bottom 12 of the dosage form.

In an embodiment, the predetermined amount of powder 40 may be a predetermined volume of powder material having a substantially uniform powder density such that the predetermined volume delivers a substantially fixed mass weight of powder material. An accurate, and reproducible mass weight of deposited amounts of powder material is important to ensure that the final dosage form consisting of two or more deposits of powder material has a consistent, accurate total amount of powder material. In embodiments where the powder material comprises an active ingredient in particulate form (e.g., a particulate pharmaceutical or drug) and the powder material comprises one or more other particulate materials, it is preferred that the particulate active ingredient is not separated from the other particulate materials.

In another embodiment, the predetermined amount of powder may be a predetermined mass weight of powder material. Also, assuming a substantially uniform powder density, the predetermined mass weight delivers a substantially fixed volume of powder material. In the embodiment shown, the predetermined mass weight of powder material provides a volume of powder material in the bottom of the available space in the recess 4 sufficient to form a substantially uniform powder layer of fixed volume. Depending on the size and shape of the bottom part of the available space in the recess 4, a first powder layer is formed consisting of a substantially uniform powder layer of a predetermined depth.

A representative example of the dosing device 24 is shown in fig. 7 as a manual dosing device 75. The manual dosing device 75 comprises a feed container or hopper 71 containing a quantity of powder material 20, an outer cylinder 73 mounted at the bottom of the hopper 71 and having an upper opening communicating with the hopper 71 and a lower opening 173, an inner cylinder 79 rotating axially within the outer cylinder 73 as indicated by the rotational arrow R-R in fig. 7. The inner cylinder 79 is configured to rotate within the outer cylinder 73 between a fill rotational position shown in fig. 8 and a dispense rotational position shown in fig. 10. The inner cylinder 79 has a cylindrical filling chamber 77 formed in the cylindrical wall of the inner cylinder 79, the cylindrical filling chamber 77 opening into the volumetric space of the feed hopper 71 when rotated to the filling rotational position, as shown in fig. 8, and opening into the lower opening 173 of the outer cylinder 73 when rotated to the dispensing rotational position, as shown in fig. 10.

Fig. 8 shows a cross-sectional view along line 8-8 of the manual dosing device 75 of fig. 7. In the filling position, the filling chamber 77 of the inner cylinder 79 communicates with the inner space of the hopper 71 to allow the powder 20 to flow into the volume space of the filling chamber 77 by gravity and to completely fill the volume space of the filling chamber 77 with a predetermined volume of the powder 177. The volume space of the filling chamber 77 is a predetermined volume for accommodating the necessary amount of powder material required for depositing a layer of powder. In some embodiments, the inner cylinder 79 and its filling chamber 77 may be replaced with another inner cylinder having a different sized filling chamber for depositing a different predetermined volume of powder. In another embodiment of the invention, the system may include a second (or more) manual metering device having filling chambers of different volumetric dimensions to accommodate the formation of different predetermined volumes of the initial and incremental layers of powder, or for containing powder material having different specific densities to achieve a target mass of powder material.

Fig. 9 shows the inner cylinder 79 in an isolated rotational position between a filling rotational position and a dispensing rotational position, wherein the powder material 177 in the filling chamber 77 is isolated from the hopper 71. Fig. 10 shows the inner cylinder 79 rotated to the dispensing rotational position to expel a predetermined volume of powder 177 (dashed line) from the filling chamber 77 by gravity through the opening 173 in the bottom of the outer cylinder 73 into the bottom of the space 5 of the recess 4 as a mass of powder material 40. Thereafter, the manual dosing device 75 may be repositioned by rotating the inner barrel 79 and the evacuated fill chamber 77 back to the isolation rotational position and then back to the fill rotational position shown in FIG. 8 to refill the fill chamber 77 with powder 20. As shown in fig. 6, the powder is deposited by gravity into the recess 4, forming a powder pile 40 above the top surface of the first bonded powder layer 61, typically, but not necessarily, in a uniform and reproducible shape, and generally having a conical shape, depending on the angle of repose of the powder material. The peaks of the mass of powder material 40 are generally below the discharge outlet 173 of the powder dosing device 24, and the surface of the powder tapers gradually towards the outer wall 9 of the recess 4.

An example of an automatic dosing device for filling a plurality of recesses in a dosing package is the rotational dosing device shown in fig. 11. The rotational dosing device 224 comprises a hopper 271 for supplying the powder material 20 and a rotating drum 275 having an outer surface 276, in which a number of filling cavities 277 is formed, which is sufficient in number to fill the recesses 4 in the blister sheet 2. The blister sheet 2 having the desired number of recesses 4 is moved (arrow) beneath the rotary metering device 224 at a speed synchronized with the rotation of the rotary drum 275, while the ports 277 are aligned with the recesses 4.

The tank 271 includes a plurality of dispensing ports, illustrated as three dispensing ports, that supply powder material into the fill cavity 277. Fig. 12A shows a cross-sectional view through the hopper 271 and rotating drum 275, showing the dispensing gate 278. The sliding door 279 dispenses powder material through a dispensing door 278 disposed at the fill point 272 of the device 224. As the rotating drum 275 rotates, each fill cavity 277 rotates toward the fill point 272. As fill cavity 277 approaches fill point 272, sliding door 279 is pulled away (small arrow) within the slot of dispensing door 278 to allow a portion of the powder material to pass through and fill cavity 277. The sliding door 279 may be oriented to be pulled apart transverse to the axis of rotation 100 (as shown) of the rotating drum 275, or opposite (or in the direction of) the movement of the blister sheet 2, or oriented to be pulled apart parallel to the axis of rotation 100.

The rotational dosing device 224 further includes a housing 274 having an arcuate inner surface opposite the outer cylindrical surface 276 between the sliding door 279 and the discharge point 273 of the device 224, covering a fill cavity 277f (fill cavity 277 filled with powder material 20) to prevent spillage of the powder material. The front edge of the housing 274 provides a means for removing excess powder dispensed into the fill cavity 277 and leveling the powder surface within the fill cavity 277 f.

In some embodiments of the rotational dosing device, a vacuum system may be included that applies a vacuum on the inner surface of the fill cavity 277 to help retain the powder material filled into the fill cavity 277.

In some embodiments, the size and depth of each filling cavity is sufficient to hold and dispense a layer of powder material 20 into each recess 4 of the blister sheet 2 to form a powder layer 61. Fig. 12B shows a rotational dosing device 375 in which each filling cavity 377 is sized to hold a volume of powder sufficient to exceed the amount of powder required to form a powder layer in the recess. In such embodiments, the device 224 further includes a volume dispensing recess to meter a predetermined volume of powder material into the oversized filling cavity. Examples of volume dispensing notches are shown in fig. 13-18 and discussed below.

In some embodiments, a sliding door or other known means may be used to limit the volumetric ratio of powder material into the filling cavity 377 to limit the outflow of powder material from the tank 271. A non-limiting example of a limiting means is a distribution gate 279.

After each filling chamber 277f (or 377 f) deposits its powder material into the empty recess 4 of the blister sheet 2, the rotating drum 275 and the filling chamber 277 (or 377) of the blister sheet 2 advance in alignment at the same linear speed. Once emptied, the filling chamber proceeds toward filling point 272. In some embodiments, the rotation of the rotary drum 275 and the advancement of the blister sheet 2 are performed constantly, and in some embodiments, the rotation of the rotary drum 275 and the advancement of the blister sheet 2 are temporarily stopped when the filling cavity reaches the filling point and/or the discharge point.

Fig. 13-18 illustrate another embodiment of an automatic dosing device 225 for filling multiple recesses in a dosing package. Fig. 13 shows an elongated tank 271 containing powder material 20. The box 271 is oriented along the width of the blister sheet 2 transverse to the direction of movement of the blister sheet 2 under the dosing means 225. Fig. 14 shows an empty tank 271 with a bottom dispensing opening that feeds a volume dispensing recess 282. The volume dispensing recess 282 includes a support frame 283 having an elongated cavity 285 and a dispensing opening 284 at a distal end. A recessed gate 286 is disposed within the elongated cavity 285 and has a recessed aperture 287 in the distal portion, and an operating means extending from the proximal portion, shown as a shaft 288 extending through a rear opening in the support frame 283. The recess door 286 is movable by an operator within the elongated chamber 285 between a filling position shown in fig. 15 and a dispensing position shown in fig. 17. In fig. 15, the powder material 20 flows under gravity to completely fill the notch aperture 287. At the same time, the blister sheet 2 is positioned below the volume dispensing recess 282 to align the empty recess 4 below the elongated cavity 284 of the support frame 283.

In fig. 16, the manipulation device is shown as a force exerted on the shaft 288, which moves (slides) the notch gate 286 and the filled notch aperture 287 distally. As the recessed gate 286 moves distally, the upper surface of the proximal portion of the body of the recessed gate 286 covers and closes the bottom dispensing opening of the elongate tank 271. As the notch door 286 continues to move distally, the filled notch aperture 287 of the notch door 286 moves in a direction aligned with the dispensing opening 284. As shown in fig. 16, when the filled recess 287 begins to overlap and align with the dispensing opening 284 of the frame, the powder material within the recess bore 287 begins to empty through the dispensing opening 284 and into the aligned recess 4. Once the recess door 286 is moved into alignment with the dispensing port 284, as shown in FIG. 17, substantially all of the powder material has fallen from the recess aperture 287, through the dispensing port 284 and into the recess 4. Once the notch aperture 287 is emptied, the blister sheet 2 is advanced to move the next empty recess 4 into alignment below the dispensing opening 284, as shown in fig. 18. Simultaneously or at the same time, the operator, shown as a force applied to the shaft 288, moves (slides) the notch gate 286 and the evacuated notch aperture 287 proximally and returns them to the filling position shown in fig. 15.

It should be appreciated that the alignment and filling of the recesses and the movement of the recess aperture between the filling and dispensing positions occurs simultaneously or at the same time in other recesses and volume dispensing recesses 282 positioned laterally along the elongated tank 271.

Fig. 19-24 illustrate another embodiment of a- > motion dosing device 226 for filling multiple recesses in a dosing package. In fig. 19, similar to the embodiment shown in fig. 13, the elongated bin 271 containing the powder material 20 is oriented along the width of the blister sheet 2, perpendicular to the direction of movement of the blister sheet 2 under the dosing device 226. Similar to the embodiment shown in fig. 14, fig. 20 shows that the empty box 271 has a bottom dispensing opening that feeds a volume dispensing recess 292 (similar to the volume dispensing recess 282). The volume dispensing recess 292 includes a support frame 293, the support frame 293 having an elongated cavity 295 and a dispensing opening 294 at a distal end. A recessed door 296 is disposed within the elongated cavity 295 and has a recessed aperture 297 in the distal portion, and a manipulation device extending from the proximal portion, shown as a shaft 298 extending through a rear opening in the support frame 293. The recessed gate 296 is movable within the elongated cavity 295 by an operator between a filling position, shown in fig. 21, and a dispensing position, shown in fig. 22. In fig. 21, powder material 20 flows under gravity to completely fill notch hole 297. At the same time, the blister sheet 2 is positioned below the volume dispensing recess 292 to align the empty recess 4 below the cavity 294 of the support frame 293.

In fig. 22, the operator, shown as a force applied to the shaft 298, moves (slides) the notch gate 296 and the filled notch aperture 297 distally and toward the dispensing opening 294 to align with the dispensing opening 294. As the recessed gate 296 moves distally, the upper surface of the proximal portion of the body of the recessed gate 296 covers and closes the bottom dispensing opening of the elongate tank 271. Once the recess door 296 is moved into alignment with the dispensing opening 294, generally all of the powder material has fallen from the recess hole 297, through the dispensing opening 284 into the recess 4, as shown in FIG. 22. In some embodiments and situations, a portion of the powder material within evacuated recess hole 297 may remain, adhere or adhere to the edges of recess hole 297. To ensure that all of the powder material is dispensed into the recess, a tamper 88 is provided, the tamper 88 having a rim 89 and a lower surface 87, disposed vertically above the dispensing opening 294 and axially aligned with the dispensing opening 294. When tamper 88 is lowered in alignment through notch hole 297 and dispensing opening 294, rim 89 and lower surface 87 clear all powder material from notch hole 297 into recess 4, as shown in fig. 23. In some embodiments, rim 89 of tamper 88 extends sufficiently to allow lower surface 87 to extend into recess 4 and contact powder layer 61. In some embodiments, the tamper 88 is sufficient to level and/or tamp the powder layer, as described in further detail herein below.

Once the notch hole 297 is emptied, the blister sheet 2 is advanced to move the next empty recess 4 into alignment below the dispensing opening 294, as shown in fig. 24. Simultaneously or at the same time, the operator is shown as a force applied to the shaft 298, which moves (slides) the notch gate 296 and the evacuated notch aperture 297 proximally and back to the filling position shown in fig. 21.

In some embodiments, the 3DP system and device may include a second or more dosing devices for dispensing a second powder material (including a different second powder material) into the recess to form a dosage form comprising two (or more) sources, types, and compositions of powder material.

Other non-limiting examples of mechanical dosing and/or metering devices are described in U.S. patent nos. 9,409,699 and 9,828,119, and U.S. patent publications 2017/032068 and 2018/0031410, the disclosures of which are all incorporated herein by reference in their entirety. The piezo needle dispensing apparatus dispenses powder that is actuated by transporting the powder material along the stainless steel tube using a standing wave driven by a piezo actuator. At the dispensing tip of the needle, a standing wave is used to spray the powder material. These devices are effective in delivering small and fixed amounts of powder material and deliver them accurately.

Other non-limiting examples of mechanical dosing and/or metering devices may include gravimetric powder dispensing/powder dosing devices, which may be from ChemSpeed Technologies @, for examplehttps://www.chemspeed.com/flex- powderdose/) The disclosure of which is incorporated herein by reference in its entirety.

In some embodiments, the method and system include means for leveling the mass of powder material within the recess. Fig. 25 shows a step of flattening a predetermined amount of the stack 40 of powder material 20 in the recess 4 into a substantially uniform powder layer 41. A leveling means is used to turn the pile 40 or other shaped deposit of powder material 20 into a substantially uniform powder layer 41. In the embodiment shown in fig. 25, the flattening means comprises a method comprising: the recess 4 and the powder mass 40 contained therein are oscillated in any one or a combination of laterally, orbital and vertically, at a frequency and at a speed sufficient to spread and disperse the powder mass 40 outwardly over the entire bottom area of the space 5 of the recess 4, and in some embodiments, into a substantially uniform powder layer 41. The method forms a first substantially uniform layer 41 of powder having a predefinable layer thickness or height "h". In a manual system, the package and its recessed portion may be shaken manually or with a vibrating table. Non-limiting examples of mechanical vibration tables, conveyors are available from Tinsley Equipment Company at the website: https:// www.tinsleycompany.com/bulk-process-equivalent/library-tables/, the disclosure of which is incorporated by reference.

In some embodiments, the powder material layer prepared within the recess has a planar surface parallel to the base of the recess. In some embodiments, the layer of powder material prepared within the recess may have a uniform thickness with a tolerance. In such embodiments, the powder material layers that are slightly non-uniform in thickness but within tolerance may be bonded with a bonding liquid into a bonded powder formulation. In some embodiments, the non-uniformity of the level of the powder material layer may be defined by the difference (variance) of the powder layer thickness from a weight average or target thickness. The minimum thickness in the powder layer and the maximum thickness in the powder layer may have a difference relative to the weight average thickness, wherein the difference is up to about a 25% difference. In some embodiments, the difference is up to about 20% difference, up to about 15% difference, and in some embodiments, up to about 10% difference, and the difference may be at least 5%, at least 10%, at least 15%, or at least 20% difference. For example, a powder material layer having a weight average (target) thickness of 0.50mm may have a thickness with a 20% tolerance, wherein the minimum and maximum thickness of the powder layer is 0.40mm to 0.6mm, while the bonding of the powder material to the bonding liquid is still effective. In another example, a powder material layer having a weight average (target) thickness of 1.0mm may have a thickness with a 15% tolerance, wherein the minimum and maximum thickness of the powder layer is 0.85mm to 1.15mm, while the bonding of the powder material to the bonding liquid is still effective. Fig. 26 shows a support plate 15 that may be used to secure and support one or more recesses 4 of the blister package 1, including, but not limited to, during powder deposition and layering, during adhesive liquid deposition, during solvent removal, and during any other process steps of the present method and system. A port or opening 16 in the support plate 15 provides a receptacle for receiving and supporting the recess 4 and blister package 1 on an upper surface 17 of the support plate 15. In some embodiments, the recesses arranged in a pattern may be aligned with the openings 16 in the support plate 15 arranged in a pattern. In some embodiments, the openings 16 arranged in this pattern include a plurality of rows and a plurality of columns. In some embodiments, the opening 16 extends into and through the entire thickness of the support plate 15. In some embodiments, the opening 16 extends into the thickness of the support plate 15 and only partially through the thickness of the support plate 15 to provide a blind hole.

Fig. 27 shows an embodiment of a support plate 115, which support plate 115 comprises openings 116 arranged in a pattern through an upper surface 117, thereby forming blind holes into the support plate 115. The support plate 115 has three columns and four rows of blind holes 116, and a series of longitudinal access holes 118 extending from the end edges 114 of the support plate 115, and a central hole 119, the central hole 119 extending through the thickness along the columns of four blind holes, through the material between each of the adjacent holes 116, such that the access holes 118 and the central hole 119 communicate with each blind hole 116 in the columns. Vacuum is applied to the access holes 118 communicating with each blind hole 116 through intermediate holes 119 to draw and secure the blister pack 1 to the upper surface 117 of the support plate 115.

Fig. 28 shows a non-limiting example of a powder leveling means as a vibration means 230 for providing lateral oscillations (oscillates) to the recesses 4 in the blister sheet 1. In the embodiment shown, the blister sheet 1 is supported within a support plate 15. The device has a strike arm 232, the strike arm 232 having a U-shape and being attached at a proximal end to a pivot post 231 oscillating about an axis "a" causing a base 233 of the U-shaped strike arm 232 to oscillate laterally "b" into a side edge of the support plate 15. The lateral tapping may provide leveling and improve the uniformity of the powder layer of powder material formed within the recess. The frequency and extent of the rotational oscillation "a" of the pivot post 231 is controlled to provide the frequency and impact force of the base 233 oscillating against the support plate 15 to provide effective leveling of the powder layer without ejecting the powder from the recess or unevenly drifting the powder within the recess.

An alternative means for leveling a stack of powder into a substantially uniform powder layer within a recess is shown in fig. 29-32.

Fig. 29-32 show an alternative flattening device for flattening the stack 40 of powder 20 into a substantially uniform powder layer within the recess 4. The levelling means 80 is shown arranged in a position above the open-ended recess 4, in which a stack 40 of a predetermined amount of powder material 20 has been deposited on the centre of the first bonded powder layer 61. Leveling device 80 is employed to form a substantially uniform layer of powder material from the unevenly disposed mass of powder material 40. Layering device 80 includes a vertical rotor shaft 82 that is driven by an electric rotating device (not shown). Non-limiting examples of such electric rotating devices include servo motors. The powder horizontal member extends horizontally and radially from the bottom of the rotor shaft 82 to a distal end substantially the radius of the recess 4. The powder horizontal member rotates about the axis of the rotor shaft 82 while descending into the mass of powder material 40 to form a substantially uniform powder layer within the recess 4.

As shown in fig. 29, the powder horizontal member may include a brush assembly including a disk 84 attached to a lower end of the rotor shaft 82 at a center thereof and configured to rotate about an axis of the rotor shaft 82. In one non-limiting embodiment, the disk 84 includes a plurality of brushes 86 attached to the lower surface 81 of the disk 84 and extending downwardly from the lower surface 81 of the disk 84. The plurality of brushes 86 are typically positioned in a pattern to maintain the center of gravity of the disk 84 at its attachment point to the rotor shaft 82. In alternative embodiments, a single circular pad may be attached to the lower surface 81 of the circular disk 84. The plurality of layered brushes 86 are made of a material that avoids sticking of particles of powder material to avoid sticking during operation. In one embodiment, the plan view diameter specified by the plurality of layered brushes 86 is the same or substantially the same diameter dimension as the plan view area of the bottom of the space 5 within the recess 4.

The rotor shaft 82 may also be integrally assembled within a housing or shroud (not shown) that extends around the periphery of the disk 84 to form a dust barrier during leveling of the powder material.

As shown in fig. 30 and 31, the plurality of brushes or paddles 86 in the central region 85 of the rotating disc 84 contact the peak and upper portion of the stack 40 as the brush assembly rotates and descends into the recess 4. The particles of powder 20 are then thrown partly and radially outwards towards the wall 9 of the recess 4. Once the rotating disc 84 descends towards the final height shown in fig. 31, any raised portions of the mass of powder material 40 in the center of the recess 4 are thrown against the wall 9 or spread out towards the wall 9 and the top surface of the powder material in the mass 40 is substantially flattened into a plane to form a substantially uniform powder layer 42. The type and elasticity of the brush or other material contacting the powder particles, the rotational speed of the rotating disc 84, and the rate of descent of the flattening device 80 down into the recess should be selected and controlled to avoid throwing excessive particles against the inner surface of the wall 9 of the recess, which may result in excessive accumulation of powder along the wall 9. Once the substantially uniform layer 42 of powder material is formed, the delamination apparatus 80 may be lifted from the space 5 within the recess 4, as shown in fig. 32.

In alternative embodiments, the powder level member may comprise a single powder level member, including the use of a blade or rod.

In another embodiment, the powder horizontal member may have a curvature in the plane of rotation.

In another embodiment, the powder level member may have a curved and non-linear lower edge, e.g. concave or convex, in order to sweep the surface of the mass of powder material into a layer of powder material having the same surface profile.

In some embodiments, the dosing device 24 may include a device that both dispenses a predetermined amount of powder material and forms the powder into a substantially uniform layer of powder within the recess. An example of such a device is shown in fig. 33-41.

Fig. 33-38 illustrate an alternative means of both dispensing a predetermined amount of powder material 20 and forming the powder into a substantially uniform powder layer within the recess 4. The layer deposition apparatus 90 shown may simultaneously perform the step of dispensing a predetermined amount of powder material 20 and the step of forming the powder into a substantially uniform powder layer within the recess 4. Examples of layer deposition apparatus are described in U.S. patent 10,071,372 and U.S. patent publication 2017/0312179, the entire disclosures of which are incorporated herein by reference.

The layer deposition device 90 is shown in fig. 33 in position to collect the necessary volume of powder material from the powder hopper 91 filled with powder. The layer deposition apparatus 90 includes a suction cylindrical body 92 having an outlet suction end 93 and an inlet powder tip 94 with an inlet rim 96. Positioned within body 92 at powder end 94 is a perforated plate 95 that extends across the entire cross-section of the interior of body 92. Perforated plate 95 may be a woven or nonwoven screen material, or a material such as: has a porosity with a plurality of channels leading from its surface facing the inlet to its surface facing the vacuum to form an air porous medium. The dimensions of the channels are small enough to allow free flow of air while preventing powder material 20 from entering therein during operation.

The inlet-facing surface of perforated plate 95 is positioned at a distance or depth "h" in the axial direction from inlet rim 96 to define a cylindrical powder absorbing volume 97. In one embodiment, the axial position of perforated plate 95 may be moved toward or away from inlet edge 96 to predetermined change cylindrical powder absorbing volume 97 to obtain a predetermined amount of powder material for forming a substantially uniform powder layer.

As also shown in fig. 34, suction is applied to the interior of the body 92 by a remote vacuum source, as indicated by the arrow with the word "vacuum". The vacuum source may be regulated by any means known in the art that can provide a controlled amount of vacuum. The vacuum in body 92 causes air to enter through inlet end 94 through perforated plate 95.

Fig. 34 shows a step of filling the powder absorption volume 97 with the powder 20 by placing the inlet end 94 in the powder hopper 91. The vacuum causes the incoming air to draw particles of powder material 20 from hopper 91 into inlet end 94 where they are drawn and deposited in powder absorption volume 97. As long as the vacuum is maintained, the powder volume 140 in the powder absorbing volume 97 remains attracted by the incoming air towards the porous plate 95 as the layer deposition device 90 is removed from the powder hopper 91 (as shown in fig. 35) and moved to a position above the recess 4 (as shown in fig. 36).

Fig. 36-38 show a filling device 90 that deposits a volume 140 of powder material 20 into the space 5 of the recess 4. In the illustrated embodiment, the inlet end 94 of the body 92 is configured to be inserted downwardly into the recess 4 during powder deposition and layering. In one embodiment, as shown in fig. 37, during powder deposition and layering, the inlet end 94 of the body 92 is placed directly above the most recently bonded powder layer (here bonded powder layer 61) within the recess 4. As the inlet end 94 is lowered toward this newly bonded powder layer 61, the application of vacuum is carefully controlled and the vacuum level is reduced to reduce the risk of the incoming air flow damaging or interfering with the matrix of powder and binder bonding the powder layer 61. When the vacuum applied to the body 92 is removed, the amount 140 of powder 20 in the powder-absorbing volume 97 "drops" due to gravity onto the upper surface of this last, first bonded powder layer 61, forming a second powder layer 42 as shown in fig. 38 when the filling device 90 is pulled up and away from the recess 4.

The body 92 may be configured with a thin and/or tapered wall at the inlet end 94 to minimize the space that the wall occupies between the deposited amount 42 of powder and the inside of the wall 9 of the recess 4. Otherwise, an excessive wall thickness at the inlet end 92 may result in the deposited powder layer 42 having a lateral diameter (width) smaller than the diameter (width) of the recess inner wall 9, which may result in the outer peripheral wall of the powder deposited layer 42 falling into the gap between them, as shown in fig. 38.

In an alternative embodiment, the inner diameter of the powder absorbing volume 97 may be matched to the same diameter as the diameter of the inner wall 9 of the recess 4 at the bottom of the space 5. In this embodiment, although not shown, the inlet end 94 of the body 92 is positioned above the newly bonded powder layer 61 within the recess 4. When the vacuum applied to the body 92 is removed, the amount 140 of powder 20 in the powder absorbing volume 97 will drop a short distance due to gravity onto the upper surface of the newly bonded powder layer 61, while the powder area matches the top surface area of the newly bonded powder layer 61. Although this embodiment avoids the gaps of the previous embodiments, the free fall of the powder volume through the air space creates turbulence that affects the uniformity of the resulting powder deposit.

The alternative embodiment shown in fig. 39-41 is to solve the problem of the gap in the previous embodiment while avoiding the problem caused by the free fall of the powder volume onto the top surface of the newly bonded powder layer 42. In another embodiment, the porous plate 195 shown in fig. 39 is configured with an upturned annular peripheral deposit that creates an additional annular powder volume space 197 at the periphery of the powder absorption volume space 97 and allows the powder 240 within the powder absorption volume space 197 to absorb an additional annular amount of powder 297 included within the volume space 197. As shown in fig. 40, with the inlet end 194 placed just above the newly bonded powder layer 61 in the recess 4, a vertical dashed line 198 shows the outer diameter of the additional powder in the additional annular powder volume space 197, which vertical dashed line 198 is located inside the diameter of the recess 4 wall 9 shown by dashed line 199. However, as annular powder 297 is substantially filled in the additional annular powder volume 197, the annular gap between

diameters

198 and 199 is fully filled, so that a substantially uniform powder layer 42 is deposited, as shown in FIG. 41.

Fig. 42 shows a step of applying a bonding liquid onto the space 5 and onto the first powder layer 41 (fig. 25). In a preferred embodiment, the bonding liquid is applied using 3D printing methods and techniques, such as those described in U.S. patent nos. 6,471,992, 6,945,638, 7,300,668, 7,875,290, and 8,088,415, the disclosures of which are incorporated herein by reference. In the illustrated embodiment, the first predetermined amount of bonding liquid is deposited by ejecting droplets 30 of liquid from printing nozzles 32 of an inkjet printing nozzle assembly 33. The droplets 30 of binding liquid bind the particles of powder material into a cohesive powder-liquid matrix, thereby forming the first wetted powder layer 51 into a substantially uniform layer.

In a typical embodiment, the bonding liquid includes an amount of solvent that is excess to remain in the resulting wet powder layer 51, which is preferably removed to form the final bonded powder layer. Fig. 43 shows the recess 4 provided in the port or opening 16 of the support plate 15 during removal of solvent from the wetting powder layer.

A liquid removal system is provided that is adapted to receive one or more blister sheets containing one or more layers of wetted powder or an intact 3DP dosage form within a recess to remove liquid therefrom. The liquid removal system may be a treatment area through which one or more blister sheets are directed. For example, the liquid removal system may remove or reduce liquid from the incremental print layer in the form of a 3DP in the process. Alternatively, the liquid removal system may be another treatment area not directly related to the three-dimensional printing system, such as a temporary holding or storage area, where the three-dimensional printed blister sheet is placed and dried under ambient conditions. In some embodiments, the liquid removal system is one or more dryers.

Fig. 43 shows several means for heating or applying heat to the wetted powder layer 51 formed in the recess 4 to remove excess solvent liquid, typically by evaporating excess liquid solvent into the gas or vapor carried away from the dry powder layer. The means for removing the liquid solvent shown may include heating the excess solvent in the wetted powder layer to evaporate the excess solvent liquid into various forms of gas or vapor V. The means shown may be selected from one or more of the following: convective heat transfer using hot air 35 transferred up or down towards the wetted powder layer 51; conductive heat transfer using a hot liquid or hot air, such as heated liquid 36, on the bottom side of the recess 4 for conducting heat 38 through the sheet material of the recess 4 and into the wetting powder layer 51; and radiant heating using infrared radiation 39 from a suitable infrared source, the infrared radiation being transmitted down into the recess and/or through the sheet material of the recess 4 and into the wetting powder layer 51, for example, as described in U.S. Pat. nos. 6,990,748, 6,047,484 and 4,631,837, the disclosures of which are incorporated herein by reference in their entirety.

In some embodiments, the drying means comprises a plurality of infrared light emitting sources arranged in a pattern for emitting infrared energy towards the upper surface of the blister sheet 1. A blister sheet 1 comprising a wetted powder material deposited in the recess is transferred into the housing and positioned at the determined coordinates. In some embodiments, the pattern form and coordinates of the upper surface of the wetted powder material are detected and mapped to form a dry profile. An Infrared (IR) light source is illuminated and controlled to emit IR light at the upper surface of the wetted powder material in an exclusive manner. The time and intensity of the emitted infrared light is maintained to heat and evaporate the upper surface and evaporate moisture and other solvents from the volume of wetted powder material. In some embodiments, a mask having shaped openings arranged in a pattern for allowing IR energy to pass through is used to control the IR light emitted onto the wetting powder. In some embodiments, the light emitted through the mask is focused using a refractive material such as a lens. In some embodiments, the IR light source comprises a high resolution IR light emitter that is controlled to emit IR light in a pattern.

Fig. 44 shows an embodiment of a dryer 415 suitable as a liquid removal system. The dryer includes a housing 416, with a plurality of heating elements 417 and a conveyor system 418 contained within the housing 416. The housing includes an inlet 420 and an outlet 419,3DP blister sheet 422 and optionally their respective support plates are guided through the inlet 420 and the outlet 419 by a conveyor. In some embodiments, the dryer includes one or more covers 421 for the inlet and/or outlet. The dryer optionally includes an exhaust system 423 for removing steam and/or a source of heated air 424 for providing heated air to the dryer.

Fig. 45-49 illustrate the deposition of an additional predetermined amount of powder 20 that is deposited or formed as a substantially uniform powder layer. Fig. 45 shows a second substantially uniform powder layer 42 arranged on a first bonded powder layer 61 within the recess 4, while fig. 47 shows a fifth substantially uniform powder layer 45 deposited on four previously formed bonded powder layers 61, 62, 63 and 64. A droplet 30 or stream of bonding liquid is deposited onto the powder layer to form additional wetted powder layers, including a second wetted powder layer 52 as shown in fig. 46 and a fifth wetted powder layer 55 disposed over the four previously formed bonding powder layers 61, 62, 63 and 64, as shown in fig. 48.

After each successive wetting powder layer is formed in the recess, any excess solvent from the binding liquid may be removed from the wetting powder layer as described above. Fig. 49 shows the fifth, uppermost bonding powder layer 65 after removal of excess solvent from the uppermost wetting powder layer 55. Once the final dosage form 10 has been printed, the dosage form is covered with a lidding sheet 8 and sealed in the recess 4 of the package to form a dosage form blister 1a, as also shown in fig. 49.

In some embodiments, some or all of the wetted powder layers may be formed sequentially, and a single drying step may be performed on some or all of the wetted powder layers to remove the solvent. In certain embodiments, the removal of excess solvent may be performed continuously or simultaneously during material deposition.

In fig. 49, the final dosage form comprising a bonded powder matrix 10 consisting of five bonded powder layers 61-65 has a shape and size that substantially conforms to the interior space of the recess 4.

In one embodiment of the invention, the inner surface of the packaging sheet 6 forming the recess 4 may comprise a release agent. The release agent provides means for the outer wall 11 and the bottom surface 12 (see fig. 1) of the dosage form 10 to be easily released from these inner surfaces or to avoid adhesion to these inner surfaces, said outer wall 11 and bottom surface 12 facing the inner surface and the closed end 7, respectively, of the wall 9 of the recess 4. The release agent may be a compound applied to the inner surface of the recess prior to dose printing. One non-limiting example is

Is released from the dosage form without residual compound on the recess 4. The release agent may also be a compound of the plastic material of the packaging sheet 6, an inherent property or application feature, such as a plastic film with anti-adhesive properties laminated to the inner surface of the sheet.

In certain embodiments, the release agent is characterized by a low surface energy when compared to the surface tension of the deposition liquid, thereby limiting or modulating the degree of wetting on the inner surface of the recess and inhibiting movement of the binding liquid along the periphery of the dosage form.

In some embodiments, to deposit a bonding liquid having a surface tension in the range of 40 to 50mN/m, the interior surface of the recess desirably has a surface energy of less than 40mN/m, and more particularly less than 35 mN/m. In some embodiments, to deposit a bonding liquid having a surface tension in the range of 30 to 40mN/m, the interior surface of the recess desirably has a surface energy of 29mN/m or less, more particularly less than 25 mN/m. If a multi-layer cavity material is used, for example polyvinyl chloride/polytrifluoroethylene (PVC/PCTrFE), it is desirable to place a PCTrFE sheet (30.9 mN/m) on the inner surface of the recess and a PVC sheet (41.5 mN/m) on the outside of the recess.

In general, the surface energy of the release agent (or plastic) is desirably 1mN/m to 5mN/m, or 5mN/m to 10mN/m, or 10mN/m or more lower than the surface tension of the deposition fluid. Table 1 shows a list of common polymers and their data (sources: http:// surface-tension. De/solid-surface-energy. Htm).

If the release agent is other material applied to the packaging sheet forming the recess, the release agent is suitable for consumption when a water-based binding liquid is used and may be selected from the group formed by oils, waxes or fatty acids, metal salts of fatty acids, or fatty acid esters. Suitable release agents may be selected from the following: such as those listed in USP/NF related pharmacopoeias, excipient guidelines, GRAS (generally recognized as safe) lists of materials, or food additive regulations. Exemplary mold release agents can include, but are not limited to, magnesium stearate, stearic acid, glyceryl distearate (glyceryl dipalmitostearate), glyceryl distearate (glyceryl distearate), glyceryl palmitostearate, glyceryl bisbehenate, mono-and diglyceride mixtures, glyceryl stearate, beeswax (beeswax), carnauba wax (carruba wax), cetyl esters wax (cetylester wax), or combinations thereof.

Although a single dosage form 10 has been shown formed within a single recess 4, the methods and apparatus described herein may be used to form multiple dosage forms within corresponding recesses of a packaging material, such as a blister sheet as shown in fig. 1. The array of blister-type recesses may comprise any arrangement or pattern of recesses 4, as is known in the art.

In another embodiment, as shown in fig. 50-53, the printheads and nozzles of the 3D printing assembly may be configured to apply droplets 30 of bonding liquid onto any particular portion of the substantially uniform powder layer. In fig. 50, the bonding liquid is applied only at the side portions 48 of the second (or subsequent or any) powder material layer 42 to form the peripheral portions of the wetted powder 58 and leave the central portion 71 of the non-wetted, non-bonded powder. After the wetted powder 58 is dried to the peripheral portion of the bond powder 68, an additional layer of powder may be applied. Fig. 51 shows the third powder layer 53 applied on a layer below it, the side portions 68 comprising a binding powder material but the powder central portion 49 of which does not have any binding liquid. As shown in fig. 52, droplets 30 of bonding liquid are deposited onto the third powder layer 53 to form a wetted powder layer 53 without applying a substantial amount of liquid that may penetrate down into the non-wetted, non-bonded powder center portion 49 of the second powder material layer 42. In such an embodiment, the bonded powder portion in the peripheral portion 68 of the second bonded powder layer 62 and/or the wetted (or bonded) powder layer 53 thereabove and the first bonded powder layer 61 therebelow, shown in fig. 53, provides a resilient structure sufficient to accommodate only the powder volume, such as the powder central portion 49, while maintaining the structural integrity of the resulting dosage form 10.

Fig. 54-59 illustrate an alternative embodiment of a method of forming a dosage form within the recess 4 of the blister pack 1, which includes a shaped, bonded powder core 106, with a hard and resilient adhesive coating 120 surrounding the core 106, as shown in fig. 59.

Fig. 54 shows a first uniform layer 41 of powder material deposited within the recess 4, over the lower coating of binding liquid at the closed end of the interior space 5 of the recess 4, thereby forming a wetted powder base layer 50 covering the inner surface of the closed end 7, and the remainder of the powder layer 41 described above. Selected nozzles 132 of 3D printing assembly 33 are configured to selectively apply drops or streams 34 of bonding liquid at the peripheral edge of first powder layer 41, wetting the powder at the peripheral edge of powder layer 41 to form wetted peripheral coating 151. In the embodiment shown, the central portion of the powder layer 41 is not wetted by the droplets 34 of the second binding liquid. The second binding liquid may be the same as the binding liquid previously described for wetting the uniform powder layer, or may be different. Typically, the concentration of the second binding liquid applied on the peripheral portion 151 is greater than the concentration of the binding liquid applied to wet the powder layer. In one embodiment, the amount of binding liquid is sufficient to coat and conceal substantially all of the powder particles to form a liquid continuous wetted powder.

In one embodiment, the droplets 34 are applied using an inkjet printing system 33 in which a plurality of printing nozzles 132 are arranged in an array, typically one or more linear rows of nozzles 132. The recess 4 containing the powder layer 41 and the array of nozzles 132 are moved relative to each other, the recess 4 passing horizontally under the array of nozzles 132, while the droplets 34 are deposited in a timed predetermined pattern such that the droplets 34 of the binding liquid are applied only at the peripheral portion of the powder layer 41. In one embodiment, the array of nozzles 132 is stationary, while the one or more recesses 4 move horizontally under the nozzles 132. In an alternative embodiment, the recess 4 is stationary and the array of nozzles 132 passes horizontally over the recess 4. As the recess 4 passes under the array of nozzles 132, selected ones of the nozzles along the array 33 are activated to present droplets 34 only when the corresponding portion of the powder layer 41 passes under, the droplets 34 eventually presenting a ring-shaped pattern of liquid adhesive 151 formed on the peripheral portion of the powder layer 41.

In another embodiment, not shown, the droplets 34 are applied in a fixed and uniform manner from a liquid nozzle, while the recess 4 containing the powder layer 41 is placed under the nozzle. The recess 4 and the nozzle are typically stationary, although in alternative embodiments they may be moved simultaneously and synchronously. In a typical embodiment, the nozzle emits droplets as an annular pattern of hollow cones.

In another embodiment, the droplets 34 are applied using a liquid flow nozzle configured to deposit a volume of the second binding liquid without precisely controlling the droplet size of the inkjet nozzle. Typically, the ejection velocity of the droplets of such liquid flow nozzles is significantly slower than the velocity of the inkjet ejection system. A non-limiting example of a liquid flow nozzle is an ultrasonic deposition nozzle, which may be from Sonotek Corporation of milton, new york at accumix ^TM The system is obtained. These nozzles result in low velocity droplets, resulting in less disturbance to the powder material, with minimal overspray and a wide range of volume ratios and median droplet sizes (diameters). Spray patterns are available in a variety of modes, including wide and narrow cone patterns, and focused linear streams.

Fig. 55 shows that droplets 30 of the first binding liquid as described above are applied to a central portion of the first powder layer 41, thereby forming a first wetting powder layer 51. The wetted peripheral portion 151 generally surrounds and encapsulates the central wetted portion of the wetted powder layer 51. In some embodiments, the order of applying the bonding liquid may be reversed by: a bonding liquid is first applied to the central portion of the powder layer 41 to form a wetted powder portion, and then a second bonding liquid is applied to form a wetted peripheral portion 151.

Once dried, the wetted peripheral portion 151 is formed into a stable cured or elastomeric peripheral coating portion 161 having a cohesive powder layer portion 61 therein, as shown in fig. 56. The cycle is repeated to deposit three additional uniform powders, each of which is wetted with a droplet or stream 34 of the second binding liquid on the peripheral edges of the respective second, third and fourth powder layers and wetted within the respective central portions of the powder layers to form a wetted powder layer. Each layer may be treated separately or in groups of two or more layers to remove excess binder solvent to form second, third and fourth bonded powder layers 62, 63 and 64 having cured or elastomeric

peripheral coating portions

162, 163 and 164, respectively, as shown in fig. 56. Also shown in fig. 56, after depositing the fifth uniform powder layer 45, selected nozzles 132 of the 3D printing assembly 33 are configured to apply drops or streams 34 of the second bonding liquid at the peripheral edges of the uppermost fifth powder layer 45, wetting the powder at the peripheral edges to form a wetted peripheral coating 155. In fig. 57, the remaining portion of the uppermost uniform powder layer 45 is contacted with droplets 30 of the first binding solution to form a wetted powder layer center portion 55 having a wetted peripheral coating 155.

In an alternative embodiment, the wetted peripheral coating 155 may be treated first to remove excess binder solvent from the wetted peripheral coating 155 and form a cured or elastomeric peripheral coating portion 165 prior to wetting the remaining non-wetted portion of the fifth uniform powder layer 45 with the binding liquid.

As shown in fig. 58, a droplet or stream 34 of the second binding liquid is deposited on the top central portion of the uppermost fifth powder layer 55, contacting and overlapping the cured or resilient peripheral coating portion 165, and forming a wetted coating 158. Fig. 59 shows the final dosage form 110, after drying or curing the wetted coating 158 on the top portion of the uppermost cohesive powder layer 65, with a top elastomeric coating 168, the top elastomeric coating 168 completing the formation of the outer coating 120 around the formed binder core 106.

In another embodiment, FIG. 60 shows a cross-sectional view of a tamper 88, the tamper 88 having a lower surface 87 defining a cavity and a corresponding rim 89, ready to be aligned with the top layer 45 of powder material in the recess 4. The cross-sectional shape of the tamper 88, and thus the shape of the lower surface 87 of the cavity, is configured to match the cross-sectional shape of the desired dosage form being prepared. A non-limiting example of a tamper is described in international publication WO2017/034951, the disclosure of which is incorporated herein by reference in its entirety. In the illustrated embodiment, the shape of the cavity is a concave circle, but in other embodiments may be a concave oval, square, rectangle, or any other geometric shape. The rim 89 is configured to align within the inner wall 9 of the recess 4 when placed against the upper surface of the top powder layer 45 as shown by the arrow, forming the upper surface of the shaped top powder layer 46 into a corresponding convex inverse shape as shown in fig. 61. The tamper 88 can be lowered (downward arrow in fig. 61) onto the loose deposited powder to smooth, shape, or alter the surface thereof. In some embodiments, the tamper 88 is lowered once and raised, or may be lowered two or more times to the same or different depths to effect one or a series of tamping steps. In some embodiments, the tamper can be lowered into contact with the powder and advanced downward based on a linear (vertical) travel distance, the extent of which affects the tamping and/or leveling of the deposited powder layer.

The level or degree of compaction may result in an increase in the areal density of the powder material or wetted powder material. In some embodiments, the density of the powder material may be increased by up to about 33% by ramming the powder material. In some embodiments, the density increase achieved by compacting the powder material is up to about 30%, or up to about 25%, or up to about 20%, and may be at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%. The desired or actual increase in density may be varied or selected based on the composition of the powder material and/or the portion of the dosage form formed from the compacted powder material. In some embodiments, the tamping can increase the density of the deposited layer of powder material by at least 0.05 grams per cubic centimeter (g/cc), including at least 1.0g/cc, and up to about 1.5g/cc, including up to about 1.0g/cc. In some embodiments, tamping can increase the density of the wetted powder material by at least 0.03 grams per cubic centimeter (g/cc), including at least 0.05g/cc, at least 1.0g/cc, and up to about 1.5g/cc, including up to about 1.0g/cc.

In some embodiments, the tamper may be lowered into contact with the powder and advanced based on a detected or measured linear force or pressure on the tamper, the extent of which affects the degree of compaction and/or leveling of the deposited powder. In some embodiments, as the tamper is lowered, the tamper 88 rotates in one rotational direction as shown in FIG. 61. Rotation of the tamper 88 while decreasing increases the uniformity of the depth of the powder layer and the uniformity of the area compaction of the powder. Movement of tamper 88 can be controlled by any control system known in the art. After ram 88 is raised, as shown in fig. 63, recess 4 containing the bonding powder layer and the shaped top powder layer 46 may be moved to a print area where a bonding liquid may be applied to the convex powder material layer 46 to form the final uppermost bonding powder layer 157.

Although the lower surface of tamper 88 that contacts the 3DP article in the process is depicted as a concave circular shape, the lower surface of the tamper may be flat or other non-flat shape, meaning shaped (or contoured) as desired.

In an alternative embodiment as shown in fig. 64 and 65, a tamper may be used to shape the uppermost wetted powder layer. After depositing the fifth uniform powder layer 45, selected nozzles of the 3D printing assembly 33 are configured to apply droplets 30 of bonding liquid onto the uppermost fifth powder layer 45, wetting the powder to form an uppermost wetted powder layer 46, as shown in fig. 64. In some embodiments, the uppermost wetted powder layer 46 may be shaped, tamped or marked using a tamper. As shown in fig. 65, tamper 88 may be lowered and placed against the upper surface of the uppermost wetting powder layer 64 to form an uppermost bonding powder layer 157.

In some embodiments, the tamper and tamper system can be used to form one or more, such as a series of layers of tamped powder or layers of tamped wetted powder, within the recess. The one or more compacted powder layers may be compacted uniformly or unevenly, resulting in one or more uniform or uneven densified powder layers, or one or more uniform or uneven densified wetted powder layers.

In some embodiments, one type or shape of tamper may be used on one or more powder layers or wetted powder layers, and a different type or shape of second tamper may be used on a different one or more powder layers or wetted powder layers to provide a different aesthetic or performance effect or characteristic to the resulting dosage form.

In some embodiments, the rotary compaction device can include a laterally extending cylindrical outer surface from which compactors arranged in a pattern extend radially outward. The positioning of the compactors can be moved axially to adjust the distance each compactor extends from the outer surface to allow the compactors to extend downwardly into the recess by different distances.

An automatic compaction apparatus may be provided for compacting a plurality of dispensed powder layers within the recess. One example is the rotary tamping device shown in fig. 66, which is shown in cross-section on the blister sheet 2 in fig. 67. The rotary tamping device 284 includes a rotary drum 285 having an outer surface 286 in which a plurality of tamps 287 are disposed, the number of tamps 287 being sufficient to tamp each of the plurality of recesses 4 in the blister sheet 2. The blister sheet 2 with the desired number of depressions 4 moves under the rotary tamping device (sideways arrow), in synchronism with the rotation of the rotary drum 285, with the tamper 287 aligned with the pair of depressions 4. The tamper is of a size and shape sufficient to extend into each recess to tamper the layer of powder material 41 in each recess 4 to form a compacted layer of powder 47.

Other tamper faces of various sizes, shapes and contours are contemplated. The tamper face may include raised (or possibly recessed) letters, numbers, or other symbols to provide an imprint in the outer or inner incremental layers of the 3DP article to reflect the contour of the tamper face in reverse (i.e., raised features on the tamper face create lowered features on the incremental layers and vice versa). The tamper face may include a specific pattern or texture that has a similar purpose, namely creating and embossing into the inner or outer incremental layers of the 3DP article. In certain embodiments, the pattern or texture of features on the tamper face allows powder from more than one incremental layer to be intermixed into the same horizontal thin layer of the 3DP article. For example, in the case where there are two consecutive incremental layers of each→different powder, not each powder remains substantially in its respective layer when displaced by the action of a non-smooth tamper face having raised or recessed features, but rather one or both powders may be displaced up or down into an adjacent incremental layer. In some embodiments, this may include the recesses created in the instantaneous increment layer of the first powder being subsequently filled with the second powder in a next powder spreading step, or this may include raised areas in the instantaneous increment layer of the first powder but extending into the space allocated to the next increment layer with the second corresponding powder, or a combination of both.

In some embodiments, the tamper system consists of a tamper arranged in a pattern that is positioned to align over a recess arranged in a corresponding pattern. In some embodiments, the tamper arranged in this pattern moves in a vertical direction, orthogonal to the base of the recess. In some embodiments, the compactors arranged in this pattern move in unison as a component, but in some embodiments, each of the compactors moves independently of the other compactors. In some embodiments, the tamper arranged in the pattern is fixed in lateral position and alignment with the recess arranged in the pattern is provided by manipulating the recess arranged in the pattern (e.g., a blister package sheet having the recess 4 arranged in a pattern). In some embodiments, the recesses arranged in the pattern are fixed in lateral position and alignment with the tamper arranged in the pattern is provided by manipulating the tamper arranged in the pattern. In some embodiments, both the tamper arranged in the pattern and the recess arranged in the pattern can be independently manipulated into alignment with each other.

In general, the 3DP device assembly and/or apparatus may include various subsystems, including one or more three-dimensional print build systems, and optionally one or more liquid removal systems. The system may include one or more three-dimensional print build systems, one or more liquid removal (drying) systems, and optionally one or more other systems. In some embodiments, the device component may comprise one or more (sub) systems selected from the group consisting of: one or more upper compaction systems, one or more control systems, and one or more inspection systems. For example, in certain embodiments of the recess 3DP system, it is not necessary to have a harvesting system since substantially all of the powder material entering the recess is contained in the corresponding dosage form within the recess. Similarly, in certain embodiments of the recess 3DP system, since the tablets are formed in situ in the package, it is not necessary to eject the formed tablets, transport them, and/or feed them into a separate package.

Fig. 68 shows a first non-limiting embodiment of a 3DP device assembly, consisting of a linear device assembly 501. The conveyor system 511 is configured to move a blister sheet that is typically supported on a support plate. Non-limiting examples of conveyors are described in U.S. publication 2014/0065194 (Aprecia Pharmaceuticals Company), the disclosure of which is incorporated herein by reference in its entirety, wherein the described build module may comprise a support plate or a module for transporting a support plate on which one or more blister sheets are supported.

The apparatus assembly 501 includes a powder bin 521 and a rotational dosing device 531 as described herein, or other embodiments disclosed herein for dispensing powder material into a recess. The apparatus assembly 501 includes a leveling device or apparatus 541, shown as a vibrating plate, or other embodiment of a powder level member, device or apparatus described herein. The device assembly 501 includes printing equipment or apparatus 551, such as an inkjet printing system as described herein. The apparatus assembly 501 includes a drying device 561, which is illustrated as a radiant heating device, or other embodiments of a drying device as described herein.

Fig. 69 shows a second non-limiting embodiment of a 3DP device assembly 502, which 3DP device assembly 502 is comprised of at least two

assemblies

551 and 552 arranged in series. Each of the

assemblies

551 and 552 are arranged in a continuous loop onto and from which the supported blister sheet 215 may be conducted. The assembly 551 comprises a powder box 521 and a rotary dosing device 531, a levelling device 541, a printing device 551 and a drying device 561. The assembly 552 includes a powder tank 522 and a rotational dosing device 532, a leveling device 542, a printing device 552, and a drying device 562. In some embodiments, the supported blister sheet 215 may be passed through the first assembly 551 one or more times, or through the second assembly 552 one or more times, or through both the first assembly 551 and the second assembly 552 one or more times. In some embodiments, the powder material dispensed from powder bin 521 is different than the powder material dispensed from powder bin 522. In some embodiments, the powder dispensing apparatus may be a different powder dispensing apparatus, and the dispensing apparatus of the first assembly 551 may be different than the dispensing apparatus of the second assembly 552. In some embodiments, the powder leveling device 541 of the first assembly 551 may be different from the powder leveling device 542 of the second assembly 552. In some embodiments, the bonding liquid applied to the powder material from printing device 551 is different from the bonding liquid applied to the powder material from printing device 552. In some embodiments, the drying device 561 is different from the drying device 562.

Fig. 70 shows a third non-limiting embodiment of a 3DP device assembly 503 consisting of a continuous loop 512 onto which a supported blister sheet 215 may be guided or from which it may be guided (shown by the green arrow). The assembly 553 comprises a powder box 521 and a rotary dosing device 531, and a powder leveling device 541 along a first portion of the endless conveyor 512, and a printing device 551 and a drying device 561 on a second portion of the endless conveyor 512. The supported blister sheet 215 may be brought into the system 503 along a first portion of the endless conveyor 512 and removed from the system 503.

Fig. 71 shows a fourth non-limiting embodiment of a 3DP device assembly 504, which consists of a first continuous loop 512 and a second continuous loop 513, wherein the two

loops

512 and 513 share a common conveyor section 514. The assembly 504 comprises a powder tank 521 and a rotational dosing device 531, and a printing device 551 along the common conveyor section 514. After exiting the printing apparatus 551, the supported blister sheet 215 may be directed along the outer loop 512 of the first continuous loop or along the outer loop of the second continuous loop 513. Along the first continuous loop 512 a powder levelling device 541 is arranged and along the second continuous loop 513 a drying device 561 is arranged. The supported blister sheet 215 may pass along the common conveyor section 514 and through the powder dispensing means (powder box 521 and rotational dosing means 531) and printing means 551 to form a wetted powder layer within the recess. This operation may optionally direct the supported blister sheet 215 to a leveling device 541 or a drying device 561. In some embodiments, the supported blister sheet 215 may pass through the printing device 551 without applying a bonding liquid, whereby the mass of powder material deposited in the powder dispensing system is transferred along the first continuous loop 512 to the leveling system 541 to level the powder material, and back along the common conveyor portion 514 and through the printing device 551 to form a wetted powder layer within the recess.

Fig. 72 shows a fifth non-limiting embodiment of a 3DP device assembly 505, consisting of a first continuous loop 512 and a second continuous loop 513, the two

loops

512 and 513 sharing a common conveyor section 514. The assembly 505 comprises powder dispensing means (powder box 521 and rotation dosing means 531) and levelling means 541 along the outer portion of the endless conveyor 512, and printing means 551 and a pair of drying means along the outer portion of the endless conveyor 513, consisting of a first drying means 561 and a second drying means 562. The first continuous loop 512 is used to dispense powder material into the recesses of the supported blister sheet 215 and planarize, while the second continuous loop 513 is used to dispense binding liquid onto the powder layer and dry the remaining binding liquid (or solvent in the formed tablet) from the formed tablet. The first drying means 561 and the second drying means 562 may be independently selected from any of the embodiments of the drying means described herein. The first drying device 561 may be different from the second drying device 562.

The powder may comprise one or more materials suitable for pharmaceutical or non-pharmaceutical use. In some embodiments, the powder comprises one or more pharmaceutical excipients, one or more pharmaceutically active agents, or a combination thereof. In some embodiments, the three-dimensional printed article is a pharmaceutical dosage form, a medical device, a medical implant, or other such article as described. Exemplary types of pharmaceutical excipients that may be included in the three-dimensional printed article include, for example, but are not limited to, chelating agents, preservatives, adsorbents, acidifying agents, alkalizing agents, antifoaming agents, buffering agents, colorants, electrolytes, flavoring agents, polishing agents, salts, stabilizing agents, sweeteners, tonicity adjusting agents, anti-adherents, binders, diluents, disintegrants, glidants, lubricants, opacifying substances, polishing agents, plasticizers, other pharmaceutical excipients, or combinations thereof.

One or more binders may be included in the matrix of the binding powder. The binder may be contained in the powder material or in the binding liquid. The binder is independently selected for each occurrence. Adhesion of particles to and/or by the binder occurs when the binder is in contact with the bonding liquid from the printhead, or when the binder is present in the bonding liquid (i.e., soluble). The binder is preferably water-soluble, aqueous fluid-soluble, partially water-soluble or partially aqueous fluid-soluble. In some embodiments, the printing fluid comprises 1-20 wt%, 5-15 wt%, or 8-12 wt% binder. In some embodiments, the bulk powder comprises greater than 0.1 to 10 wt%, 5 to 15 wt%, 0 to 15 wt%, 8-14 wt%, or 9-11 wt% binder. In some embodiments, the printed substrate comprises 1-20 wt%, 5-14 wt%, or 8-12 wt% binder. In some embodiments, no binder is present in the printing fluid or no binder is present in the bulk material. Suitable binders include water-soluble synthetic polymers, polyvinylpyrrolidone (povidone), sorbitol, mannitol, xylitol, lactitol, erythritol, pregelatinized starch, modified starch, hydroxypropyl methylcellulose, and the like. The preferred binder is polyvinylpyrrolidone, such as PVP K30, modified starch (e.g., sodium starch octenyl succinate), mannitol, or a combination thereof. PVP with a K value other than 30 may be used, including, but not limited to PVP K25 and PVP K90.

In some embodiments, the powder material contained in each of the one or more powder layers is a powder material that is compositionally the same. In some embodiments, the powder material in one or more powder layers is different from the powder material in another powder layer. In such embodiments, the different composition powder materials may contain different Active Pharmaceutical Ingredients (APIs) or API placebo, or no API content.

Pharmaceutically active agents generally include physiologically or pharmacologically active substances that produce systemic or local effects or effects in animals, cells, tissues, organs, non-humans and humans.

Whenever mentioned and unless otherwise indicated, the term "active agent" includes all forms of active agent including neutral, ionic, salt, basic, acidic, natural, synthetic, diastereomeric, isomer, enantiomerically pure, racemic, hydrate, solvate, chelate, derivative, analogue, optically active, optically enriched, free base, free acid, regioisomer, amorphous, anhydrous and/or crystalline forms.

In some embodiments, the powder material composition in the powder layer may be the same. In some embodiments, one region of the powder layer may include a powder material that is compositionally different from the powder included in another region of the powder layer.

The three-dimensionally printed dosage form may comprise one, two or more different active agents. Specific combinations of active agents may be provided. Some combinations of active agents include: 1) A first drug from a first treatment category and a different second drug from the same treatment category; 2) A first drug from a first treatment category and a different second drug from a different treatment category; 3) A first drug having a first type of biological activity and a second, different drug having substantially the same biological activity; 4) A first drug having a first type of biological activity and a second, different drug having a second, different type of biological activity. Exemplary combinations of active agents are described herein.

The active agent may be independently selected at each occurrence from active agents such as: antibiotics, antihistamines, decongestants, anti-inflammatories, antiparasitics, antivirals, local anesthetics, antifungals, bactericides (amoebicidal agent), trichomonal miticides (trichomonocidal agent), analgesics, anti-arthritic agents, anti-asthmatics, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antitumor agents, antipsychotics (anti-psychic agents), antipsychotics (neuroleptic agent), antihypertensives, hypnotics, sedatives, anxiolytics (anxiolytic energizer agent), antiparkinsonants, muscle relaxants, antimalarials, hormonal agents, contraceptives, sympathomimetics, hypoglycemic agents, antilipemic agents, ophthalmic agents, electrolytes, diagnostic agents, prokinetic agents, gastric acid secretion inhibitors, antiulcer agents, antifflatulents, anticonvulsants, cardiovascular agents, or combinations thereof. Descriptions of these and other classes of useful drugs, and the list of species in each class, can be found in Martindale 37 ^th Edition (2017), the Extra Pharmacopoeia,31ST Ed. (The Pharmaceutical Press, london, 1996), the disclosure of which is incorporated herein by reference in its entirety.

Exemplary types of non-pharmaceutical excipients that may be included in the powder material may include, for example, but are not limited to, ash, clay, ceramic, metal, polymer, biological material, plastic, inorganic material, salt, other such materials, or combinations thereof.

In some embodiments, the powder comprises one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or a plurality of ingredients, each of which is independently selected at each occurrence. In some embodiments, the device assembly includes one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or a plurality of powder (or solid component) supply reservoirs.

The binding liquid applied to the powder may be a solution or a suspension. The liquid may comprise an aqueous carrier, a non-aqueous carrier, an organic carrier, or a combination thereof. The aqueous carrier may be water or an aqueous buffer, or a combination of water and one or more alcohols. The non-aqueous carrier may be an organic solvent, low molecular weight polymer, oil, silicone, other suitable material, alcohol, ethanol, methanol, propanol, isopropanol, poly (ethylene glycol), ethylene glycol, other such material, or combinations thereof. The terms liquid, binding liquid, printing fluid, binding fluid and liquid may be used interchangeably to refer to a liquid that is delivered as part of 3 DP.

In some embodiments, the device assembly includes one or more, two or more, three or more, four or more, or a plurality of reservoirs. The liquid may be colored or colorless. The liquid may include pigments, paints, dyes, hair dyes, inks, or combinations thereof. The liquid may contain one or more solutes dissolved therein. The powder and/or liquid may comprise one or more binders. In an embodiment, the bonding liquid may also comprise a binder. In some embodiments, the liquid may comprise an active ingredient.

In some embodiments, the bonding liquid may be deposited in a pattern on the upper surface of the powder layer or on the entire surface. In some embodiments, the pattern form has a shape selected from the group consisting of an annular ring, a circle, a polygon, or any other desired shape. In some embodiments, the concentration of the binding liquid (mass per unit area) applied to the upper surface of the powder layer in the form of a pattern is uniform, while in other embodiments the concentration of the binding liquid applied in one or more portions of the pattern is greater than or less than the concentration of the binding liquid applied in other portions. In some embodiments, where the thickness of the powder layer varies across the surface area, a higher concentration of binding liquid may be applied over a portion of the powder layer having a positive thickness variation (greater than the gravity average thickness) and a lower concentration of binding liquid may be applied over a portion of the powder layer having a negative thickness variation (less than the gravity average thickness). Any of the embodiments of this paragraph can be combined with any of the other embodiments described herein.

Non-limiting examples of powder materials and binding liquids are described in U.S. Pat. nos. 9,339,489, 9,492,380 and 9,314,429, the disclosures of which are incorporated herein by reference. Any of the embodiments described herein may employ a bonding liquid comprising: the water (which may include distilled and/or deionized water) may be selected from alcohols of any lower straight or branched chain alcohols having 1 to 3 carbon atoms, soluble binders, antioxidants, glycerol and surfactants or emulsifiers. The printing liquid may comprise from 1 to 25% by weight, from 5 to 20% by weight or from 10 to 15% by weight of at least one organic solvent, suitably an alcohol. Suitable alcohols may include ethanol, methanol, n-propanol, and isopropanol, or combinations thereof.

In some embodiments, the glycerol content in the binding liquid ranges from at least about 0.1% by weight up to about 20% by weight, including at least 0.5% by weight, at least 1.0% and at least 1.5% by weight, and up to about 10% by weight, including up to about 5% by weight. In some embodiments, the glycerol is present in the dosage form in an amount ranging from at least about 0.05% by weight, including at least 0.1% by weight, and at least 0.5% by weight, and up to about 5% by weight, including up to about 3% by weight, up to about 2% by weight, and up to about 1.0% by weight, based on the final weight of the dosage form.

The foregoing is a detailed description of specific embodiments of the invention. It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the present invention is not limited except as by the appended claims, and any amendments to the claims that include any elements or features of the embodiments described herein are recognized by those of ordinary skill in the art as filed on even date herewith. All embodiments disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure.

Claims

1. A method of forming a dosage form within a portion of a package for the dosage form, comprising the steps of:

1) Providing a portion of a package for a dosage form, the portion of the package comprising at least one recess,

2) Depositing a powder material comprising particles into a powder layer within the at least one recess,

3) Depositing a bonding liquid in a pattern on the powder layer within the at least one recess to bond at least a portion of the particles of the powder layer to form an incremental wetting layer; and

4) Optionally, steps 2) and 3) are repeated sequentially at least one or more times,

thereby forming the dosage form within the portion of the package for the dosage form.

2. The method of claim 1, wherein the at least one recess has a fixed shape and volume.

3. The method of claim 1 or claim 2, wherein the package comprises a sheet comprising a plurality of the recesses formed into the sheet, and wherein the recesses comprise sidewalls extending from the sheet to a closed end.

4. A method according to any one of claims 1 to 3, wherein step 4) is repeated at least three times.

5. The method of any of claims 1-4, wherein a portion of the powder material comprises particles of a binder material, and the bonding liquid bonds the particles of the binder material.

6. The method of any one of claims 1 to 5, further comprising, prior to step 2), the step of depositing a quantity of bonding liquid on at least the closed end of the recess.

7. The method of any of claims 1-6, wherein the at least one recess comprises an inner surface comprising a release agent.

8. The method of any of claims 1-7, wherein the bonding liquid comprises a volatile solvent.

9. The method of claim 8, further comprising the step of: after step 3), a portion of the volatile solvent is evaporatively removed from the incremental wetting layer to form an incremental bonding layer.

10. The method of claim 8, further comprising the step of evaporatively removing a portion of the volatile solvent from at least two or more incremental wetting layers after step 4).

11. The method of any one of claims 1 to 10, wherein the sidewall has a recess depth and each powder layer has a thickness of at least 5% and up to 50% of the recess depth.

12. The method of any of claims 1-11, wherein the dosage form is formed from a plurality of powder layers deposited within a recess and formed as a plurality of incrementally bonded powder layers.

13. The method of any one of claims 1 to 12, wherein the pattern of deposited bonding liquid comprises a peripheral pattern of bonding liquid applied to the powder layer at the inner surface of the recess.

14. The method according to any one of claims 1 to 13, further comprising the step of: a capping layer is applied over the dosage form and the at least one recess to form a sealed package for the dosage form.

15. The method of any one of claims 1 to 14, wherein the binding liquid is deposited by inkjet printing to form the dosage form.

16. The method according to any one of claims 1 to 15, wherein the step 2) of depositing a predetermined amount of powder material comprising particles into a substantially uniform powder layer within the at least one recess comprises:

1) Depositing a predetermined amount of a powder material comprising particles into the at least one recess, and

2) Forming the deposited predetermined amount of powder material into a substantially uniform powder layer within the at least one recess.

17. The method of any one of claims 1 to 16, wherein the forming step comprises tamping the newly deposited predetermined amount of powder material into the newly formed powder layer having the upper surface.

18. The method of claim 17 wherein the step of tamping employs a tamper and the upper surface is convex.

19. A method of forming a dosage form within a portion of a package for the dosage form, comprising the steps of:

1) Providing a portion of a package for a dosage form comprising at least one spatial recess;

2) Depositing a predetermined amount of powder material comprising particles into a substantially uniform powder layer within the at least one recess,

4) Sequentially repeating steps 2) and 3) at least one or more times),

20. A package comprising a film material having one or more depressions therein, the one or more depressions comprising a shaped adhesive powder form formed within the one or more depressions and conforming to an inner surface of the one or more depressions, and a peelable or removable cover sheet adhered to the film material to encapsulate the adhesive powder form in the one or more depressions.

21. The package of claim 20, wherein the binder powder formulation comprises a powder material and a portion of the powder material comprises particles of a binder material.

22. A package according to claim 20 or claim 21, wherein the binder powder dosage form comprises a plurality of incremental binder powder layers.

23. The package of claim 22, wherein the powder material within one or more of the incrementally-bonded powder layers is different from the powder material in another of the incrementally-bonded powder layers.

24. The package of any of claims 20-23, wherein the binder powder dosage form comprises one or more types of drug-containing particles.

25. The package of any of claims 20-24, wherein the binder powder dosage form comprises one, two or more different active agents.

26. The package of any of claims 20-25, wherein the combination of active agents may include: i) A first drug from a first treatment category and a different second drug from the same treatment category; ii) a first drug from a first treatment category and a different second drug from a different treatment category; iii) A first drug having a first type of biological activity and a second, different drug having substantially the same biological activity; or iv) a first drug having a first type of biological activity and a second, different drug having a second, different type of biological activity.

27. The package of any of claims 20-26, wherein the binder powder dosage form comprises two or more compositions of powder material.

28. The package of any of claims 20-27, wherein the package comprises a sheet comprising a plurality of recesses formed therein, and wherein the recesses comprise sidewalls extending from the sheet to the closed end.

29. The package of any of claims 20-28, wherein the powder composition in one region of the powder layer is compositionally different from the powder composition in another region of the powder layer.

30. A three-dimensional printing (3 DP) apparatus and system assembly for forming at least one dosage form within a portion of a package for dosage forms, comprising:

a powder deposition system configured to deposit one or more powder materials into one or more recesses of the package;

a bonding liquid application system configured to apply one or more bonding liquids onto the one or more powder materials in the one or more recesses of the package, forming one or more incremental wetting layers;

a liquid removal system configured to remove or reduce liquid from the one or more incremental wetting layers; and

a conveyor system configured to move packages through the 3DP device and system assembly.

31. The 3DP device and system assembly as set forth in claim 30, wherein said powder deposition system is disposed in a powder deposition zone, said bonding liquid application system is disposed in a bonding liquid application zone, and said liquid removal system is disposed in a liquid removal zone.

32. The 3DP device and system assembly according to claim 30 or 31, wherein at least two incremental wetting layers are formed in each of the one or more recesses of the package.

33. The 3DP device and system assembly according to any of claims 30-32, further comprising a powder leveling system configured for leveling the one or more powder materials deposited within the one or more recesses of the package.

34. The 3DP device and system assembly according to any of claims 30-33, further comprising a forming or tamping system configured for forming the one or more incremental wetting layers within the one or more recesses of the package.

35. The 3DP device and system assembly according to any of claims 30-34, further comprising a control system comprising one or more computers configured for controlling the 3DP device and system assembly.